This invention relates to the fields of pharmaceutical and organic chemistry and provides cryptophycin compounds useful for treating fungal infections.
The incidence of serious, life-threatening, fungal infections is increasing at an alarming rate. The number of Candida albicans bloodstream infections in non-teaching hospitals increased by 370% between 1980 and 1990. At the same time the incidence of bloodstream infections by C. albicans in teaching hospitals increased by 487% in the same time period. With the exception of coagulase negative staphylococci, statistically, C. albicans represents the fastest growing area of concern in hospital acquired bloodstream infections (Banerjee et al., 1991, American Journal of Medicine 91 (3B): 86S-89S).
The rising incidence of nosocomial fungal infections is being fueled by changing medical practices, including invasive surgical procedures addressing such problems as joint replacement and open heart surgery, increased use of cancer chemotherapy, and the AIDS epidemic. All of these processes compromise the immune system and provide an environment in which fungal infections can be established.
Unfortunately, the diagnosis of fungal infections is difficult and time consuming. Rather than waiting for the results of diagnostic tests, empirical antifungal therapy must frequently be initiated with a compound such as amphotericin B (which may have safety/toxicity issues) or one of the azoles to which fungal species are developing resistance. Thus, having an antifungal with a broad spectrum of activity coupled with a low toxicity profile would be very desirable.
Further, the existence of multiple drug resistance (mdr)-related genes in a non-pathological as well as in key opportunistic pathological fungi has been discovered. These genes have been termed "mdr-like" because of the homology that exists between the proteins encoded by these genes and the human mdr-1 gene product.
With the discovery of mdr-like genes in a variety of fungi, including key pathogenic fungi, such as Aspergillus flavus, Aspergillus fumigatus and Cryptococcus neoformans the prospect of discovering an antifungal agent that can have fungal mdr inhibitor activity becomes extraordinarily desirable.
Applicants have discovered agents which can be useful antifungal agents. Two particularly desired compounds are known as Cryptophycin 52 and Cryptophycin 55.
Further, Applicants provide compounds which can provide useful mdr inhibitor activity.